PROJECT SUMMARY Vascular disease is the largest single identifiable risk factor for dementia apart from age and the only one potentially preventable. Alzheimer's Disease (AD) pathology proportionately decreases with age in those with clinical dementia, implicating non-AD mechanisms as important determinants of older-onset dementia. These mechanisms are likely vascular in nature, as ?mixed vascular/AD? is more common than AD alone in older individuals. The hallmark of vascular cognitive impairment (VCI) is subcortical white matter disease, visualized on magnetic resonance imaging (MRI) as white matter hyperintensities (WMHs). WMHs are ubiquitous with age, increase the risk of dementia, stroke, and death, and are increased in AD. Our research shows WM damage extends beyond WMHs, within the immediately surrounding normal appearing white matter (NAWM). Recent studies suggest an important role of WM astrocytic dysfunction (?astrocytopathy?) in VCI. Our preliminary data support this association, and has identified changes in astrocyte phenotypes and increased tau pathology in the grey matter (GM) of cortex overlying WMHs compared with GM overlying NAWM, suggesting WMH-associated astrocytopathy contributes to both WM and GM dysfunction in both VCI and AD. We hypothesize that regional chronic cerebral ischemia results in astrocytic changes within the GM and WM, that alone and in combination with AD-associated pathologies potentiate CNS dysfunction and subsequent cognitive impairment and dementia in the elderly, and that WMHs may serve as a biomarker for these changes. We have developed a 7T postmortem MR protocol that allows for the identification and targeted sampling of WMHs and surrounding normal appearing tissue for histopathological examination that includes a detailed assessment of astrocytic changes, using brain tissue from a well-characterized cohort of Oregon Alzheimer's Disease Center subjects who come to autopsy. In Aim 1, we will identify the features of WM astrocytopathy associated with WMHs and areas in transition to becoming WMHs. In Aim 2, we will identify these changes in GM, associate these with AD-specific pathologic changes, and determine their spatial relationship to regional WMHs. In Aim 3, we will determine which regional WM and GM astrocyte abnormalities found in Aims 1 and 2 are associated with dementia status and global cognition, controlling for standard pathologies associated with neurodegenerative diseases, such as those of AD. We anticipate that the studies in human tissue will produce new insights into the relationship between VCI and AD, and suggest specific functions and functional losses of astrocytes in mediating these associations. We anticipate that treatments aimed at astrocytic protection and recovery from hypoxic injury could suggest a new spectrum of possibilities for therapeutic targets designed to prevent AD and related dementias.